They are used as adjunctive therapy, together with other drugs, in the treatment of hypertension and management of congestive heart failure. However, at low doses the use of potassium-sparing diuretics has not been found to produce a clinically significant reduction in blood pressure.[2]

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Potassium-sparing diuretics are generally used in combination with other diuretic drugs (e.g. loop diuretics) that would otherwise tend to lower the potassium levels to potentially dangerous low levels (hypokalemia). The combination therefore helps maintain a normal reference range for potassium.

The potassium-sparing diuretics are competitive antagonists that either compete with aldosterone for intracellular cytoplasmic receptor sites, or directly block sodium channels (specifically epithelial sodium channels (ENaC) by amiloride). The former prevents the production of proteins that are normally synthesized in reaction to aldosterone. These mediator proteins are not produced, and so stimulation of sodium-potassium exchange sites in the collection tubule does not occur. This prevents sodium re-absorption and potassium and hydrogen ion secretion.[3]

While not classically considered potassium-sparing diuretics, ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are anti-hypertensive drugs with diuretic effects that decrease renal excretion of potassium.[4] They work by inhibiting either the production (ACEis) or effects (ARBs) of angiotensin 2. This results in a decrease in aldosterone release, which causes potassium-sparing-diuretic-like effects similar to those of the aldosterone antagonists, spironolactone and eplerenone.